With the development of genetic recombination technology, various protein formulations became supplied in stable amounts. To ensure stability, these formulations are supplied in the dosage form of a lyophilized protein ingredient powder to be dissolved just before use in a separately packaged water-soluble diluent or in the dosage form of a protein solution formulation containing additives for improving stability.
Recently, various antibody formulations have been developed and applied for practical use, but many of the antibody formulations are used as formulations for intravenous injection. However, there are increasing demands in the medical field for developing antibody-containing formulations in the form of self-injectable formulations for subcutaneous injection.
In designing antibody-containing formulations for subcutaneous injection, the antibody concentration in the solution to be administered must be high because the injectable volume by subcutaneous injection is normally limited despite of a single high antibody dose (about 100-200 mg). Thus, there are demands for developing high-concentration antibody-containing formulations by means of lyophilization-based concentration.
JPA No. 2004-532798/WO 2002/030463/U.S. Pat. No. 6,875,432 discloses a concentrated protein formulation with decreased viscosity including a salt and/or a buffer, but describes only the effect of reducing the viscosity of the solution and nothing about stability.
JPA No. 2004-538287/WO 2003/009817 discloses a lyophilized pharmaceutical formulation prepared by lyophilizing an aqueous preparation containing an IgG antibody at a high concentration, Polysorbate, sucrose, and optionally serine and/or mannitol in a histidine buffer (pH about 5.5 to about 6.5). However, this application focuses on the stabilizing effect of sucrose, but describes nothing about the stabilizing effect by adding serine and histidine.
High-concentration antibody-containing solutions tend to form high-viscosity solutions by the properties of proteins as macromolecules and molecular interactions. Moreover, they are normally lyophilized in the presence of large amounts of lyoprotectants such as sugars during the preparation of lyophilized formulations to maintain their caking properties and stability. However, sugars enhance molecular interactions to increase viscosity, and the resulting high-viscosity formulations are difficult to dispense, draw into syringes and subcutaneously inject. Thus, novel methods for preparing stable lyophilized formulations without adding sugars are needed.